US10676498B2 - Processes for the preparation of sofosbuvir and intermediates thereof - Google Patents
Processes for the preparation of sofosbuvir and intermediates thereof Download PDFInfo
- Publication number
- US10676498B2 US10676498B2 US15/577,622 US201615577622A US10676498B2 US 10676498 B2 US10676498 B2 US 10676498B2 US 201615577622 A US201615577622 A US 201615577622A US 10676498 B2 US10676498 B2 US 10676498B2
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- United States
- Prior art keywords
- compound
- formula
- mixture
- sofosbuvir
- solvent
- Prior art date
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- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 title claims abstract description 104
- 229960002063 sofosbuvir Drugs 0.000 title claims abstract description 103
- 238000000034 method Methods 0.000 title claims abstract description 99
- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- 230000008569 process Effects 0.000 title claims description 80
- 239000000543 intermediate Substances 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 27
- 150000002367 halogens Chemical class 0.000 claims abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 142
- 239000000203 mixture Substances 0.000 claims description 113
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 104
- 239000002904 solvent Substances 0.000 claims description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 60
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 45
- 239000002585 base Substances 0.000 claims description 45
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- -1 nucleoside phosphoramidate Chemical class 0.000 claims description 27
- 229910001868 water Inorganic materials 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002777 nucleoside Substances 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 238000005859 coupling reaction Methods 0.000 claims description 18
- 230000008878 coupling Effects 0.000 claims description 17
- 238000010168 coupling process Methods 0.000 claims description 17
- 230000003301 hydrolyzing effect Effects 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 7
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 7
- 239000003880 polar aprotic solvent Substances 0.000 claims description 7
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 claims description 7
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 6
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 claims description 4
- SKAAFTUHFLUIKV-IHBJSSOOSA-N propan-2-yl (2s)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate Chemical compound CC(C)OC(=O)[C@H](C)NP(Cl)(=O)OC1=CC=CC=C1 SKAAFTUHFLUIKV-IHBJSSOOSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 claims description 3
- XQPZGJTZQDZAAW-VESQYCJJSA-N 1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O.C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O XQPZGJTZQDZAAW-VESQYCJJSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims 8
- 235000019439 ethyl acetate Nutrition 0.000 claims 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 80
- 239000007787 solid Substances 0.000 description 70
- 239000011541 reaction mixture Substances 0.000 description 60
- 239000000243 solution Substances 0.000 description 42
- 239000000047 product Substances 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 0 [1*]C1=C(OP(=O)(N[C@@H](C)C(=O)OC(C)C)OC2=CC=CC=C2)C([2*])=CC(C(=O)O[3*])=C1 Chemical compound [1*]C1=C(OP(=O)(N[C@@H](C)C(=O)OC(C)C)OC2=CC=CC=C2)C([2*])=CC(C(=O)O[3*])=C1 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 235000011054 acetic acid Nutrition 0.000 description 26
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 23
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- FHQBHYHWKPVUEZ-WBMRYOJMSA-N C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O FHQBHYHWKPVUEZ-WBMRYOJMSA-N 0.000 description 18
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 13
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 11
- 229940095102 methyl benzoate Drugs 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 238000012544 monitoring process Methods 0.000 description 10
- ARKKGZQTGXJVKW-VPCXQMTMSA-N 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 ARKKGZQTGXJVKW-VPCXQMTMSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- FSDYDBAXNANUQE-UHFFFAOYSA-N tris(2,4-dichlorophenyl) phosphate Chemical compound ClC1=CC(Cl)=CC=C1OP(=O)(OC=1C(=CC(Cl)=CC=1)Cl)OC1=CC=C(Cl)C=C1Cl FSDYDBAXNANUQE-UHFFFAOYSA-N 0.000 description 9
- VEIZCOCBSDFTNM-AXFFKAMTSA-N 2-(dimethylamino)ethyl 3,5-dibromo-4-[[[(2S)-1-oxo-1-propan-2-yloxypropan-2-yl]amino]-phenoxyphosphoryl]oxybenzoate Chemical compound BrC=1C=C(C(=O)OCCN(C)C)C=C(C=1OP(=O)(OC1=CC=CC=C1)N[C@H](C(=O)OC(C)C)C)Br VEIZCOCBSDFTNM-AXFFKAMTSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 7
- 150000004795 grignard reagents Chemical class 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 235000010323 ascorbic acid Nutrition 0.000 description 6
- 239000011668 ascorbic acid Substances 0.000 description 6
- 229960005070 ascorbic acid Drugs 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 6
- 235000006408 oxalic acid Nutrition 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- XMEQDAIDOBVHEK-UHFFFAOYSA-N 3-bromo-4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(Br)=C1 XMEQDAIDOBVHEK-UHFFFAOYSA-N 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OBWLCMWQELMODI-JOVKWUTKSA-N CC(C)OC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=CC(NC=O)=NC2=O)[C@](C)(F)[C@@H]1O)OC1=CC=CC=C1.[Ar] Chemical compound CC(C)OC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=CC(NC=O)=NC2=O)[C@](C)(F)[C@@H]1O)OC1=CC=CC=C1.[Ar] OBWLCMWQELMODI-JOVKWUTKSA-N 0.000 description 4
- DYMUVSHXXPHBBM-QLPJSJKDSA-N CC1=NC(=O)N([C@@H]2O[C@H](CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC3=CC=CC=C3)[C@@H](O)[C@@]2(C)F)C=C1 Chemical compound CC1=NC(=O)N([C@@H]2O[C@H](CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC3=CC=CC=C3)[C@@H](O)[C@@]2(C)F)C=C1 DYMUVSHXXPHBBM-QLPJSJKDSA-N 0.000 description 4
- SMNKAIIWMVGZAI-RPWKAPHTSA-N C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C=CC(NC=O)=NC1=O.[Ar] Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C=CC(NC=O)=NC1=O.[Ar] SMNKAIIWMVGZAI-RPWKAPHTSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 3
- HHVVVJWHBRMURI-OQRQYOSKSA-N CC(C)OC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@@H](N2C=CC(NC(=O)C3=CC=CC=C3)=NC2=O)[C@](C)(F)[C@@H]1O)OC1=CC=CC=C1 Chemical compound CC(C)OC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@@H](N2C=CC(NC(=O)C3=CC=CC=C3)=NC2=O)[C@](C)(F)[C@@H]1O)OC1=CC=CC=C1 HHVVVJWHBRMURI-OQRQYOSKSA-N 0.000 description 3
- RIWZPRTYNKBXOR-NIVRMLGLSA-N CC1O[C@H](CO)[C@@H](C)[C@@]1(C)F Chemical compound CC1O[C@H](CO)[C@@H](C)[C@@]1(C)F RIWZPRTYNKBXOR-NIVRMLGLSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910006124 SOCl2 Inorganic materials 0.000 description 3
- MXEQSUUFNWPUJH-RDWHIKKYSA-N [(2r,3r,4r,5r)-5-(4-benzamido-2-oxopyrimidin-1-yl)-3-benzoyloxy-4-fluoro-4-methyloxolan-2-yl]methyl benzoate Chemical compound O([C@H]1[C@]([C@@H](O[C@@H]1COC(=O)C=1C=CC=CC=1)N1C(N=C(NC(=O)C=2C=CC=CC=2)C=C1)=O)(F)C)C(=O)C1=CC=CC=C1 MXEQSUUFNWPUJH-RDWHIKKYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000003821 enantio-separation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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- A61K9/00—Medicinal preparations characterised by special physical form
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- C07B63/02—Purification; Separation; Stabilisation; Use of additives by treatment giving rise to a chemical modification
Definitions
- the present disclosure provides new procedures and intermediates for the preparation of Sofosbuvir.
- Sofosbuvir referred to herein as compound 1, L-alanine, N—[[P(S),2′R]-2′-deoxy-2′-fluoro-2′-methyl-P-phenyl-5′-uridylyl]-, 1-methylethyl ester, or (2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, having the following formula,
- Sofosbuvir and its isomer act as prodrugs and are converted through a series of in vivo transformations to an active triphosphate metabolite.
- Sofosbuvir is described in U.S. Pat. No. 7,964,580. Processes for preparation of sofosbuvir and/or the phosphoramidate intermediates are described in WO 2008/121634, WO 2010/135569, WO 2011/123645, WO 2011/123668, WO 2012/012465 and WO 2002/057425.
- WO 2008/121634 describes a process for preparing sofosbuvir by coupling a substituted phosphochloridate compound with the nucleoside analogue, 2′-deoxy-2′-fluoro-2′-C-methyluridine.
- the product is obtained as mixture of diastereomers (comprising sofosbuvir and the corresponding Rp isomer) which are separated using chiral chromatography.
- the other publications disclose other processes, some of which comprise coupling a single diastereomer of the phosphoramidate intermediate with the nucleoside analogue to afford sofosbuvir.
- WO2010/135569 and WO 2012/012465 specifically disclose use of isopropyl ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate and isopropyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate for the preparation of sofosbuvir by coupling with the nucleoside analog.
- Use of the above mentioned phosphoramidate intermediates in the coupling reaction has several drawbacks.
- isopropyl ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate poses a safety concern and use of isopropyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate requires its preparation from the expensive raw material pentafluorophenol.
- Prior art processes typically involve the preparation of single diastereomers of the phosphoramidate, achieved by either Dynamic Kinetic Resolution for converting the undesired diastereomer to the desired diastereomer, or use of preferential crystallization for isolation of one of the diastereomers. While the former has several advantages in terms of yield, to date it was realized for only a few phosphoramidates, whereas the latter requires additional processing steps. Further, the reactions typically employ toxic or costly reagents and are not suitable for industrial scale.
- the present invention provides a process for the preparation of a nucleoside phosphoramidate comprising a step of reacting a compound of formula 2:
- R 1 and R 2 can independently be hydrogen or halogen, provided that at least one of R 1 and R 2 is a halogen; and R 3 is selected from the group consisting of methyl, ethyl and C 1-3 alkyl substituted by —NR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 20 alkyl aryl, and C 6 -C 20 aryl; or R 4 and R 5 together with the nitrogen form a ring, with a nucleoside of formula 8:
- base is a naturally occurring or modified purine or pyrimidine base represented by any of the following structures:
- R 1 , R 2 , R 3 are independently selected from the group consisting of: H, F, Br, I, OH, OR, SH, SR′, NH 2 , NHR′, NR′ 2 , C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and halogenated C 2 -C 6 alkynyl;
- the present disclosure provides novel intermediates of formula 2 that can be advantageously used in the preparation of nucleoside phosphoramidates, in particular Sofosbuvir:
- R 1 and R 2 can independently be hydrogen or halogen, provided that at least one of R 1 and R 2 is a halogen; and R 3 is selected from the group consisting of methyl, ethyl and C 1-3 alkyl substituted by —NR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 20 alkyl aryl, and C 6 -C 20 aryl; or R 4 and R 5 together with the nitrogen form a ring.
- the compound of formula 2 can be:
- R 1 and R 2 can independently be hydrogen or halogen, provided that at least one of R 1 and R 2 is a halogen; and R 3 is selected from the group consisting of methyl, ethyl and C 1-3 alkyl substituted by —NR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of: C 1 -C 6 alkyl, or R 4 and R 5 together with the nitrogen form a ring.
- the present disclosure provides compounds 2a, 2b, 2c and 2d of the following structures:
- the present disclosure also provides processes for preparing the compound of formula 2.
- the present disclosure provides isolated compounds of formula 2a-2d.
- the compounds are in solid form.
- the disclosure relates uses of the compound of formula 2 in the preparation of nucleoside phosphoramidates, particularly Sofosbuvir.
- the compounds of formula 2 are compounds 2a, 2b, 2c, or 2d, particularly, compounds 2a, 2b and 2c, and more particularly compound 2a.
- the disclosure relates to compounds of formula 2 for use in the preparation of nucleoside phosphoramidates, particularly sofosbuvir.
- the compounds of formula 2 are compounds 2a, 2b, 2c, or 2d.
- the disclosure relates to processes employing said intermediates for preparing nucleoside phosphoramidates, particularly sofosbuvir.
- the disclosure provides sofosbuvir prepared by the processes of the disclosure.
- the disclosure provides crystalline forms of compound 7a-Sp:
- an X-ray powder diffraction pattern substantially as depicted in FIG. 1 or FIG. 2 characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 1 or FIG. 2 ; an X-ray powder diffraction pattern having peaks at 7.3, 9.7, 11.1, 14.6 and 19.0 degrees two theta ⁇ 0.1 degrees two theta.
- the disclosure provides crystalline forms of compound 7a-Sp characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 4 ; X-ray powder diffraction pattern having peaks at 6.5, 7.6, 9.2, 16.1, 17.5, 18.4, 18.8 and 19.9 degrees two theta ⁇ 0.1 degrees two theta.
- the disclosure further provides crystalline forms of the compound 7a-Sp for the preparation of sofosbuvir.
- the disclosure further provides the use of the crystalline forms of compound 7a-Sp for the preparation of sofosbuvir.
- the present disclosure provides a process for the isolation or purification of sofosbuvir comprising crystallising sofosbuvir from a solvent system comprising an aliphatic (preferably C 1 -C 6 ) alcohol and water, and more preferably wherein the sofosbuvir is crystallised from a solvent system comprising isopropyl alcohol and water.
- FIG. 1 shows an X-ray powder diffractogram (“PXRD” or “XRPD”) of Form 1 of compound 7a-Sp.
- FIG. 2 shows an X-ray powder diffractogram of Form 1 of compound 7a-Sp, in the range 3-36 degrees two-theta.
- FIG. 3 shows a DSC thermogram of Form 1 of compound 7a-Sp.
- FIG. 4 shows an X-ray powder diffractogram (“PXRD” or “XRPD”) of Form 2 of compound 7a-Sp.
- nucleoside phosphoramidates preferably Sofosbuvir.
- WO 2008/121634 discloses the use of the phosphochloridate intermediate to obtain a mixture of diastereomers comprising sofosbuvir and the corresponding Rp isomer.
- the desired diastereomer was subsequently separated using chiral chromatography. Replication of that process by the applicant of the present disclosure proved the ratio of the diastereomers designated herein as Sp/Rp ratio (before chiral chromatography) to be 70:30.
- the processes of the present disclosure exhibit high diastereoselectivity and afford a mixture of diastereomers comprising sofosbuvir and the corresponding Rp isomer in a Sp/Rp ratio ranging from about 85:15 to about 95:5.
- the obtained mixtures can be further separated to afford highly pure sofosbuvir by means of crystallization. Therefore, the processes of the present disclosure can be adapted to production in an industrial scale, i.e., greater than 1 kilogram scale.
- the term “substantially pure” relates to a compound, such as any one of compounds 1-7, having a purity, measured as % area HPLC, of about 95% or more. In some embodiments, the term relates to compounds having a purity of about 95% or more. In other embodiments, the term relates to compounds having a purity of about 97% area by HPLC. In further embodiments, the term relates to compounds having a purity of about 99% area by HPLC. In yet other embodiments, the term relates to compounds having a purity of about 99.3% area by HPLC. In still further embodiments, the term relates to compounds having a purity of about 99.8% area by HPLC.
- the term “substantially free of” means that the compounds, such as a compound of formula 2, contain about 20% (w/w) or less of a specified impurity.
- the compound, such as a compound of formula 2 contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0.2% (w/w) or less of a specified impurity.
- the XRPD measurements are taken using copper K ⁇ radiation wavelength 1.5418 ⁇ .
- DSC measurements are obtained at a heating rate of 10° C./minute, under a nitrogen flow of 50 mL/min.
- the term “isolated” in reference to the intermediates of the present disclosure, their salts or solid state forms thereof corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
- a mixture enriched with the Sp isomer or “enriched Sp mixture” in reference to compounds of the present disclosure, refers to a mixture comprising more than about 50% of the Sp isomer of the compounds.
- a thing e.g., a reaction mixture
- room temperature often abbreviated “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
- room temperature is from about 20° C. to about 30° C., or about 22° C. to about 27° C., or about 25° C.
- the processes or steps may be referred to herein as being carried out “overnight.” This refers to time intervals, e.g., for the processes or steps, that span the time during the night, when the processes or steps may not be actively observed.
- the time intervals are from about 8 to about 20 hours, or about 10 to about 18 hours, or about 16 hours.
- reduced pressure refers to a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.
- chlorinated solvent refers to a C 1 -C 6 chlorinated hydrocarbon.
- the chlorinated solvents are selected from the group consisting of carbon tetrachloride, dichloromethane (CH 2 Cl 2 ), dichloroethane, chlorobenzene, and chloroform.
- one pot process refers to a continuous process for preparing a desired product, in which penultimate product is converted to the desired product in the same vessel.
- protecting group refers to a grouping of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group. Examples of protecting groups can be found in Green et al., “Protective Groups in Organic Chemistry”, (Wiley, 2 nd ed. 1991) and Harrison et al., “Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley and Sons, 1971-1996).
- the amount of solvent employed in chemical processes, e.g., reactions or crystallizations, may be referred to herein as a number of “volumes” or “vol” or “V.”
- a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
- this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
- v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding MTBE (1.5 v/v) to a 100 mL reaction mixture would indicate that 150 mL of MTBE was added.
- the modifier “about” should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.”
- the term “about” may refer to plus or minus 10% of the indicated number and includes the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” means from 0.9-1.1.
- R 1 and R 2 are independently hydrogen or halogen, provided that at least one of R 1 and R 2 is halogen; and R 3 is selected from a group consisting of methyl, ethyl, and C 1-3 alkyl substituted by —NR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 20 alkyl aryl, and C 6 -C 20 aryl; or R 4 and R 5 together with the nitrogen form a ring.
- halogen or “halide” refers to fluoride, chloride, bromide or iodide. In certain embodiments, the halogen is bromide or iodide.
- Alkyl refers to a monoradical of a branched or unbranched saturated hydrocarbon chain and can be substituted or unsubstituted.
- Lower alkyl groups may contain 1-6 carbon atoms or 1-4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.
- Alkoxy refers to the O-(alkyl) group where the alkyl group is defined above.
- Aryl refers to phenyl and 7-15 membered monoradical bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
- Aryl groups can be substituted or unsubstituted. Examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-SH-benzocycloheptenyl.
- An aryl group may contain 6 (i.e., phenyl) or 9 to 15 ring atoms, such as 6 (i.e., phenyl) or 9 to 11 ring atoms, e.g., 6 (i.e., phenyl), 9 or 10 ring atoms.
- the “ring” formed with R 4 and R 5 refers to a 4- to 9-membered ring.
- the ring contains the nitrogen atom from the NR 4 R 5 group and carbon atoms.
- the compound of formula 2 is:
- R 1 and R 2 are independently hydrogen or halogen, provided that at least one of R 1 and R 2 is halogen; and R 3 is selected from a group consisting of methyl, ethyl, and C 1-3 alkyl substituted by —NR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of: C 1 -C 6 alkyl, or R 4 and R 5 together with the nitrogen form a ring.
- the present disclosure provides compounds 2a, 2b, 2c and 2d of the following structures:
- any one of compounds 2a, 2b, 2c and 2d is isolated in solid form. In other embodiments, any one of compounds 2a, 2b, 2c and 2d is crystalline.
- any one of compounds 2a, 2b, 2c and 2d is substantially pure.
- the present disclosure provides the use of a compound of formula 2 for the preparation of nucleoside phosphoramidates.
- the present disclosure provides the use of a compound of formula 2 for the preparation of sofosbuvir.
- the disclosure provides the use of any one of compounds 2a, 2b, 2c and 2d as described above for the preparation of sofosbuvir.
- the disclosure provides a compound of formula 2 for use in the preparation of nucleoside phosphoramidates.
- the disclosure provides a compound of formula 2 for use in the preparation of sofosbuvir.
- the disclosure provides any one of compounds 2a, 2b, 2c and 2d for use in the preparation of sofosbuvir.
- the present disclosure provides processes for the preparation of the compound of formula 2 comprising reacting phenyl phosphorodichloridate with (S)-isopropyl-2-amino-propanoate or an acid addition salt thereof (preferably the HCl salt) to obtain (2S)-isopropyl-2-((chloro(phenoxy)phosphoryl)amino)propanoate in-situ, designated herein as compound 3, which is subsequently reacted with a compound of formula 4 (wherein R 1 , R 2 and R 3 are as described above) as depicted in Scheme 1.
- Suitable bases may include, for example, trimethylamine, triethylamine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine etc. Particularly the base is triethylamine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine etc. In some embodiments, the base is triethylamine.
- Suitable solvents may include, for example, dichloromethane, methyl-tert-butylether, acetonitrile, or ethyl acetate.
- the solvent is selected from dichloromethane and methyl-tert-butyl ether. In other embodiments, the solvent is dichloromethane.
- Suitable bases may include, for example, trimethylamine, triethylamine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine etc. and particularly triethylamine, diisopropylethylamine, N-methylimidazole, or N-methylmorpholine, etc.
- the base is triethylamine.
- Suitable solvents may include, for example, dichloromethane, methyl-tert-butylether, acetonitrile, and ethyl acetate.
- the solvent is selected from dichloromethane and methyl, tert-butyl ether.
- the solvent is dichloromethane.
- any one of compounds 4a, 4b, 4c or 4d is reacted with compound 3 to obtain any one of compounds 2a, 2b, 2c or 2d, respectively.
- the present disclosure further provides novel and efficient processes, employing these advantageous intermediates, for the preparation of nucleoside phosphoramidates, such as sofosbuvir.
- the present disclosure provides processes for preparation of nucleoside phosphoramidates comprising a step of reacting a compound of formula 2 with a nucleoside, designated herein compound 8.
- base is a naturally occurring or modified purine or pyrimidine base represented by any of the following structures:
- R 1 , R 2 , R 3 are independently selected from the group consisting of: H, F, Cl, Br, I, OH, OR, SH, SR′, NH 2 , NHR′, NR′ 2 , C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and halogenated C 2 -C 6 alkynyl;
- the disclosure provides processes for preparation of nucleoside phosphoramidates comprising a step of coupling any one of compounds 2a, 2b, 2c or 2d with compound 8.
- a compound of formula 2 such as any one of compounds 2a, 2b, 2c or 2d, can be as an about 1:1 mixture of the diastereomers or as a mixture enriched with the Sp isomer.
- the present disclosure provides processes for the preparation of sofosbuvir comprising a step of reacting a compound of formula 2 with a nucleoside. According to the processes of the present disclosure, sofosbuvir is obtained in high yields of about 50%.
- a compound of formula 2 is coupled with 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione designated herein compound 5.
- the disclosure provides processes for the preparation of sofosbuvir comprising a step of coupling a compound of formula 2 with 2′-deoxy-2′-fluoro-2′-C-methyluridine 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione designated herein as compound 5 to afford a mixture of diastereomers comprising sofosbuvir and a step of isolating sofosbuvir as depicted in scheme 2.
- a compound of formula 2 is used as an about 1:1 mixture of the diastereomers or as a mixture enriched with the Sp isomer.
- Suitable bases may include, for example, non-alkoxy bases such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, and lithium diisopropylamide, and Grignard reagents such as (lower alkyl)Mg(halogen), which include, but are not limited to, MeMgCl, iPrMgCl, tBuMgCl, etc. Particularly the Grignard reagent may be MeMgCl or tBuMgCl.
- the base is selected from Grignard reagents such as (lower alkyl)Mg(halogen) which include, but are not limited to, MeMgCl, iPrMgCl, t-BuMgCl, etc, and preferably MeMgCl or tBuMgCl.
- the base is t-BuMgCl.
- Suitable solvents may include, for example, tetrahydrofuran, 2-methyl THF, methyl, t-butyl ether, glyme, diglyme, toluene, etc.
- the solvent is selected from tetrahydrofuran, 2-methyl THF, and methyl, t-butyl ether.
- the solvent is selected from tetrahydrofuran, methyl t-butyl ether, glyme, diglyme, toluene, or particularly wherein the solvent is selected from tetrahydrofuran and methyl t-butyl ether In other embodiments, the solvent is THF.
- the step of isolating sofosbuvir may be performed by crystallization.
- any one of compounds 2a, 2b or 2c is reacted with compound 5 to obtain sofosbuvir.
- the disclosure provides processes for preparation of sofosbuvir comprising a step of reacting a compound of formula 2 with a compound of formula 6, wherein Ar is substituted or unsubstituted aryl, followed by a step of hydrolyzing the coupling product, designated herein formula 7, wherein Ar is substituted or unsubstituted aryl to obtain sofosbuvir.
- a compound of formula 2 is used as an about 1:1 mixture of the diastereomers or as a mixture enriched with the Sp isomer.
- Suitable bases may include, for example, non-alkoxy bases such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, and Grignard reagents, such as (lower alkyl)Mg(halogen), which include, but are not limited to, MeMgCl, iPrMgCl, tBuMgCl, etc, and preferably MeMgCl, tBuMgCl, etc.
- non-alkoxy bases such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, and Grignard reagents, such as (lower alkyl)Mg(halogen), which include, but are not limited to, MeMgCl, iPrMgCl, tBuMgCl, etc, and preferably MeMgCl, tBu
- the base is selected from Grignard reagents, such as (lower alkyl)Mg(halogen), which include but not limited to MeMgCl, iPrMgCl, tBuMgCl, etc, and preferably MeMgCl, tBuMgCl, etc.
- the base is t-BuMgCl.
- Suitable solvents may include, for example, tetrahydrofuran, 2-methyl THF, methyl, t-butyl ether, glyme, diglyme, or toluene, etc.
- the solvent is selected from tetrahydrofuran, 2-methyl THF, and methyl, t-butyl ether.
- the solvent is Suitable solvents may include, for example, tetrahydrofuran, methyl, t-butyl ether, glyme, diglyme, or toluene, etc. In certain embodiments, the solvent is selected from tetrahydrofuran, and methyl, t-butyl ether. In other embodiments, the solvent is THF.
- the hydrolysis step is carried out in the presence of a hydrolyzing agent.
- Suitable hydrolyzing agents may include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, ascorbic acid, oxalic acid, formic acid or phosphoric acid etc, preferably the hydrolyzing agent is hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, ascorbic acid or oxalic acid.
- the hydrolyzing agents are selected from acetic acid, ascorbic acid, or oxalic acid, etc., for acidic conditions.
- about 60% aqueous acetic acid at about 85-90° C. is used for hydrolysis.
- the acid solution may comprise from about 10% to about 80% of acid.
- about 30% aqueous acetic acid at about 85-90° C. is used for hydrolysis
- the step of isolating sofosbuvir may be performed by crystallization.
- any one of compounds 2a, 2b or 2c is reacted with a compound of formula 6 to obtain sofosbuvir.
- the process comprises a step of reacting a compound of formula 2 with N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide, designated herein as compound 6a, followed by a step of hydrolyzing the coupling product, designated herein as compound 7a, to obtain sofosbuvir.
- the disclosure provides processes for the preparation of sofosbuvir comprising a step of reacting a compound of formula 2 and a compound of formula 6, wherein Ar is substituted or unsubstituted aryl, followed by a step of isolating the Sp isomer of the coupling product, designated compound 7, wherein Ar is substituted or unsubstituted aryl, which is further hydrolyzed, to obtain sofosbuvir.
- a compound of formula 2 can be used as a 1:1 mixture of the diastereomers or as a mixture enriched with the Sp isomer.
- Suitable bases may include, for example, non-alkoxy bases such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, and Grignard reagents such as (lower alkyl)Mg(halogen), which include, but are not limited to, MeMgCl, iPrMgCl, tBuMgCl, etc, and preferably MeMgCl or tBuMgCl.
- non-alkoxy bases such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, and Grignard reagents such as (lower alkyl)Mg(halogen), which include, but are not limited to, MeMgCl, iPrMgCl, tBuMgCl, etc, and preferably MeMgCl or tBuMgCl
- the base is selected from Grignard reagents, such as (lower alkyl)Mg(halogen), which include, but are not limited to MeMgCl, iPrMgCl, tBuMgCl, etc, and preferably MeMgCl or tBuMgCl.
- the base is t-BuMgCl.
- Suitable solvents may include, for example, tetrahydrofuran, 2-methyl THF, methyl, t-butyl ether, glyme, diglyme, toluene, etc.
- the solvent is selected from tetrahydrofuran, 2-methyl THF, and methyl, t-butyl ether.
- the solvent is selected from tetrahydrofuran, methyl, t-butyl ether, glyme, diglyme, and toluene. In other embodiments, the solvent is selected from tetrahydrofuran, and methyl, t-butyl ether. In other embodiments, the solvent is THF.
- the Sp isomer of a compound of formula 7 is crystallized from a solvent system comprising dichloromethane and diisopropylether.
- the Sp isomer of a compound of formula 7 may be crystallized from a solvent comprising methyl t-butyl ether, ethyl acetate, a mixture of ethyl acetate and THF, or a mixture of THF, dichloromethane and methyl t-butyl ether.
- the hydrolysis step is carried out in the presence of a hydrolyzing agent.
- Suitable hydrolyzing agents may include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, ascorbic acid, oxalic acid, formic acid or phosphoric acids etc.
- the hydrolyzing agent is: hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, ascorbic acid or oxalic acid.
- the hydrolyzing agents are selected from acetic acid, ascorbic acid, oxalic acid etc., for acidic conditions.
- about 60% aqueous acetic acid at about 85-90° C. is used for hydrolysis.
- the acid solution may comprise from about 10% to about 80% of acid.
- about 30% aqueous acetic acid at about 85-90° C. is used for hydrolysis
- any one of compounds 2a, 2b or 2c may be reacted with compound 6 to obtain sofosbuvir.
- the disclosure provides processes for the preparation of sofosbuvir comprising a step of reacting a compound of formula 2 with N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide, designated herein compound 6a, followed by a step of isolating Sp isomer of the coupling product, designated compound 7a-Sp, which is further hydrolyzed, to obtain sofosbuvir.
- the disclosure provides sofosbuvir prepared by any one of the processes described above.
- the disclosure provides a process for preparation of compound 6 from compound 9 comprising selective deprotection of the hydroxyl protected groups.
- the process can be illustrated by the following Scheme 5.
- Suitable bases may include, but are not limited to, for example alkali/alkaline hydroxides and carbonates such as LiOH, NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 .
- the base is NaOH.
- the amount of base may range from about 1 equivalent to about 4 equivalents, preferably 2 equivalents of base may be used.
- Suitable solvents may include, but are not limited to, polar aprotic solvents such as, THF, MTBE, pyridine, acetonitrile.
- the solvent may be THF.
- the solvent may comprise of a mixture of a polar aprotic solvent, or a mixture of a polar aprotic solvent and an alcohol, preferably mixture of a polar aprotic solvent and an aliphatic alcohol, more preferably a mixture of a polar aprotic solvent and a C 1 -C 6 aliphatic alcohol, and most preferably a mixture of THF and methanol or a mixture of acetonitrile and methanol.
- the process may be carried out at a temperature of from about ⁇ 25° C. to about 20° C., preferably at about ⁇ 15° C.
- the disclosure provides a process for the preparation of compound 6a from (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (8a) comprising selective deprotection of the hydroxyl protected groups.
- the reaction is carried out in the presence of a NaOH (base) in THF (solvent) at a temperature of about ⁇ 15° C.
- the disclosure provides a process for the crystallization of compound 6a from toluene, a mixture of toluene and THF, MTBE, ethyl acetate, mixture of ethyl acetate and THF, and a mixture of acetonitrile and water.
- the crystallization is carried out in the presence of ethyl acetate.
- the disclosure provides for the use of compound 6a, prepared by the process of the disclosure, for preparation of sofosbuvir.
- the disclosure provides a crystalline form, designated form 1, of the Sp isomer of the compound of formula 7a (7a-Sp).
- Form 1 of 7a-Sp may be characterized by data selected from: an X-ray powder diffraction pattern substantially as depicted in FIG. 1 or FIG. 2 ; X-ray powder diffraction pattern having peaks at 7.3, 9.7, 11.1, 14.6 and 19.0 degrees two theta ⁇ 0.1 degrees two theta; and combination thereof.
- Form 1 of 7a-Sp may be further characterized by an X-ray powder diffraction pattern having peaks at 19.6, 22.3, 23.6 and 27.1 degrees two theta ⁇ 0.1 degrees two theta.
- form 1 may be further characterized by a DSC thermogram substantially as depicted in FIG. 3 or a DSC thermogram with an endothermic peak at about 153° C. ⁇ 2° C.
- the disclosure provides form 1 of 7a-Sp for use for the preparation of sofosbuvir.
- the disclosure provides the use of crystalline form 1 of compound 7a-Sp for the preparation of sofosbuvir
- the disclosure provides a crystalline form, designated form 2, of the Sp isomer of the compound of formula 7a (7a-Sp).
- Form 2 of 7a-Sp may be characterized by data selected from: an X-ray powder diffraction pattern substantially as depicted in FIG. 4 ; X-ray powder diffraction pattern having peaks at 6.5, 7.6, 9.2, 16.1, 17.5, 18.4, 18.8 and 19.9 degrees two theta ⁇ 0.1 degrees two theta; and combinations thereof.
- Form 2 of 7a-Sp may be further characterized by an X-ray powder diffraction pattern having peaks at 13.3, 15.3, 15.5 and 21.0 degrees two theta ⁇ 0.1 degrees two theta.
- the disclosure provides form 2 of 7a-Sp for use for the preparation of sofosbuvir.
- the disclosure provides the use of crystalline form 2 of compound 7a-Sp for the preparation of sofosbuvir
- the present disclosure provides a process for the isolation or purification of sofosbuvir comprising crystallising sofosbuvir from a solvent system comprising an aliphatic (preferably C 1 -C 6 ) alcohol and water, preferably wherein the alcohol is isopropyl alcohol.
- a solvent system comprising an aliphatic (preferably C 1 -C 6 ) alcohol and water, preferably wherein the alcohol is isopropyl alcohol.
- Powder X-ray Diffraction (“PXRD” or “XRPD”) Method
- the ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
- PHBA p-Hydroxybenzoic acid
- MeOH 1.5 L
- SOCl 2 35 g
- the reaction mixture was then refluxed for 12 h.
- the reaction mixture was then cooled to ⁇ 15 to ⁇ 20° C.
- Bromine (637 g, 3.98 mol) was added dropwise ensuring that the temperature of the reaction mixture was ⁇ 5 to 0° C. in 1 h.
- the reaction mixture was warmed to RT and stirred until the p-hydroxymethyl benzoate level was not more than 2%.
- L-Alanine isopropyl ester hydrochloride (166.6 g, 0.9952 mol) was charged under nitrogen atmosphere into a round bottom flask (RBF), tert-butyl methyl ether (750 mL) was added and the mixture cooled to 0° C.
- Dichlorophenylphosphate 200 g, 0.9478 mol was added.
- the reaction solution was cooled to ⁇ 10° C. to 0° C. and triethylamine (293 mL, 1.895 mol) in tert-butyl methyl ether (750 mL) was added at ⁇ 10° C. to 0° C.
- the reaction mixture was allowed to stir at 0° C. for 4 h.
- L-Alanine isopropyl ester hydrochloride (166.6 g, 0.9952 mol) was charged under nitrogen atmosphere into a round bottom flask, tert-butyl methyl ether (750 mL) was added, and the mixture was cooled to 0° C.
- Dichlorophenylphosphate 200 g, 0.9478 mol was added.
- the reaction solution was cooled to ⁇ 10° C. to 0° C. and triethylamine (293 mL, 1.895 mol) in tert-butyl methyl ether (750 mL) was added at ⁇ 10 to 0° C.
- the reaction mixture was allowed to stir at 0° C. for 4 h.
- a DBDMAB (209 g, 0.5687 mol) and tert-butyl methyl ether (750 mL) mixture was prepared under nitrogen atmosphere. This mixture was cooled to ⁇ 5 to 0° C. and triethylamine (133 mL, 0.9478 mol) was added. This solution was added to the previous reaction mixture at 0 to 5° C. under nitrogen atmosphere and stirred for 1 to 2 h at 0° C. After stirring for 2 h, water (500 mL) was added, and the organic layer was washed twice with 2.5% Na 2 CO 3 (aq) solution (500 mL) followed by 6% NaHCO 3 (aq) solution (500 mL).
- a BHMB (131.4 g, 0.5687 mol) and tert-butyl methyl ether (750 mL) mixture was prepared under nitrogen atmosphere. This mixture was cooled to ⁇ 5 to 0° C. and triethylamine (133 mL, 0.9478 mol) was added. This solution was added to the previous reaction mixture at 0 to 5° C. under nitrogen atmosphere and stirred for 1 to 2 h at 0° C. After stirring for 2 h, water (500 mL) was added and the organic layer was twice washed with 2.5% Na 2 CO 3 (aq) solution (500 mL), followed by 6% NaHCO 3 (aq) solution (500 mL).
- N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (6a) (7.5 g, 0.0207 mol), 3,5-dibromo-4-((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl benzoate (2a) (30.06 g, 0.0519 mol), and THF (81 mL).
- N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (6a) (7.5 g, 0.0207 mol), 2-(dimethylamino)ethyl 3,5-dibromo-4-((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)benzoate (2b) (33 g, 0.0519 mol), and THF (81 mL).
- DIHMB 3,5-diiodo-4-hydroxy methyl benzoate
- L-Alanine isopropyl ester hydrochloride (83.49 g, 0.4980 mol) was charged under nitrogen atmosphere into a round bottom flask (RBF), dichloromethane (400 mL) was added and the mixture cooled to 0° C.
- Dichlorophenylphosphate (DCPP) (100 g, 0.4743 mol) was added.
- the reaction solution was cooled to ⁇ 10° C. to 0° C. and triethylamine (100.8 g, 1.01 mol) in dichloromethane (400 mL) was added at ⁇ 10° C. to 0° C.
- the reaction mixture was allowed to stir at 0° C. for 4 h.
- THF layer was distilled under vacuum up to 3.5-3.75 vol of the reaction mass and ethyl acetate (60 mL) and stirred for another 1-2 hour at 22-25° C.
- the obtained material was analyzed by XRPD and identified as form 2, The XRPD pattern is presented in FIG. 4 .
- the obtained material was analyzed by XRPD and identified as form 1 of compound 7a-Sp (as confirmed by XRPD).
Abstract
Description
is an orally available, second generation uridine nucleoside analogue which inhibits the NS-5 protein of hepatitis C virus (HCV). Sofosbuvir and its isomer act as prodrugs and are converted through a series of in vivo transformations to an active triphosphate metabolite.
wherein R1 and R2 can independently be hydrogen or halogen, provided that at least one of R1 and R2 is a halogen; and R3 is selected from the group consisting of methyl, ethyl and C1-3 alkyl substituted by —NR4R5, wherein R4 and R5 are independently selected from the group consisting of: C1-C6 alkyl, C1-C20 alkyl aryl, and C6-C20 aryl; or R4 and R5 together with the nitrogen form a ring,
with a nucleoside of formula 8:
wherein the base is a naturally occurring or modified purine or pyrimidine base represented by any of the following structures:
wherein R1, R2, R3 are independently selected from the group consisting of: H, F, Br, I, OH, OR, SH, SR′, NH2, NHR′, NR′2, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 alkynyl, and halogenated C2-C6 alkynyl;
- R′ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkyl aryl, and substituted or unsubstituted aryl; and
Z is hydrogen or an oxygen protecting group.
wherein R1 and R2 can independently be hydrogen or halogen, provided that at least one of R1 and R2 is a halogen; and R3 is selected from the group consisting of methyl, ethyl and C1-3 alkyl substituted by —NR4R5, wherein R4 and R5 are independently selected from the group consisting of: C1-C6 alkyl, or R4 and R5 together with the nitrogen form a ring.
characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in
wherein R1 and R2 are independently hydrogen or halogen, provided that at least one of R1 and R2 is halogen; and R3 is selected from a group consisting of methyl, ethyl, and C1-3 alkyl substituted by —NR4R5, wherein R4 and R5 are independently selected from the group consisting of: C1-C6 alkyl, C1-C20 alkyl aryl, and C6-C20 aryl; or R4 and R5 together with the nitrogen form a ring.
wherein the base is a naturally occurring or modified purine or pyrimidine base represented by any of the following structures:
wherein R1, R2, R3 are independently selected from the group consisting of: H, F, Cl, Br, I, OH, OR, SH, SR′, NH2, NHR′, NR′2, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 alkynyl, and halogenated C2-C6 alkynyl;
- R′ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkyl aryl, and substituted or unsubstituted aryl; and
- Z is hydrogen or an oxygen protecting group.
- Scan range: 2-40 degrees 2-theta;
- Scan mode: continuous;
- Step size: 0.05 degrees;
- Time per step: 0.5 s;
- Sample spin: 30 rpm;
- Sample holder: PMMA specimen holder ring.
Differential Scanning Calorimetry (“DSC”)-Method
- Column & packing: L-11, 150 mm*4.6 mm*2.7 μm
- Buffer: 0.1% v/v Solution of ortho phosphoric acid in water
- Eluent A: Buffer, Eluent B: Methanol:Acetonitrile (78:22)
- Flow: 0.8 mL/min, Detector: 215 nm
- Gradient; Time: % Eluent B, (0-45, 30-83, 35-90, 39.9-90)
- Retention time: SBV-NHBz Rp about 18.5 min, SBV-NHBz Sp about 19.1 min
Impurity Profile Method for Sofosbuvir
- Column & packing: L-11, 150 mm*4.6 mm*2.7 μm
- Buffer: 0.1% v/v Solution of ortho phosphoric acid and 0.05% w/v Potassium hexafluoro phosphate in water
- Solvent Mixture-I Acetonitrile: Isopropyl alcohol (2:1)
- Eluent A: Buffer, Eluent B: Methanol: Solvent mixture-I (80:20)
- Flow: 0.8 mL/min, Detector: 215 nm
- Gradient; Time: % Eluent B, (0-18, 5-42, 20-70, 39.9-80)
- Retention time: SBV-Rp about 13.1 min, SBV-Sp about 14.0 min
Claims (37)
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EP3303362A2 (en) | 2018-04-11 |
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WO2016196735A3 (en) | 2017-01-12 |
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US20190218243A1 (en) | 2019-07-18 |
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